Lymphangiogenesis Is Upregulated in Kidneys of Patients With Multiple Myeloma

Abstract

Neolymphangiogenesis has recently been demonstrated in transplanted kidneys as well as in chronic interstitial nephritis and IgA nephropathy. However, its significance in kidney disease remains to be defined and a systematic study of renal lymphangiogenesis is warranted. We investigated patients with multiple myeloma (MM) presenting in the great majority with acute renal insufficiency. Controls were allograft kidney donors and patients with renal insufficiency due to acute renal failure (ARF). Lymph vessel length density (LVD) was quantified immunohistochemically by means of antipodoplanin staining followed by computer-assisted stereology. The mean LVD in kidneys of patients with MM (23.19 mm À2 ) was higher when compared with allograft donors (7.42 mm À2 , P ¼ 0.0003) and patients with ARF (6.78 mm À2 , P ¼ 0.0002). The higher LVD was significantly associated with interstitial inflammation, and the newly formed lymph vessels were accompanied by diffuse and nodular interstitial infiltrates composed mainly of CD20 þ B cells and CD27 þ plasma cells. The infiltrates in patients with MM also displayed a higher expression of the B-cell chemoattractant CXCL13. These results demonstrate for the first time that lymphangiogenesis is a prominent feature in MM kidneys and that it is associated with a significant accumulation of macrophages, CD20 þ and CD27 þ B lymphocytes. Further studies should clarify whether these changes represent a beneficial or detrimental factor in the progression of the myeloma-related kidney damage. Anat Rec, 293:1497Rec, 293: -1505

The Role of Lymphatic Vessels in Renal Injury

“…Consistent with the data from rodent models, the number of lymphatic vessels was found to be increased in the cortex of the human kidney during chronic diseases [25][26][27][28]. This was studied in various forms of chronic kidney diseases like IgA nephropathy, diabetic nephropathy, lupus nephritis, ANCA-associated glomerulonephritis and tubulointerstitial nephritis [27,28].…”

Lymphatic Vessels Enhancing Adaptive Immunity Deteriorates Renal Inflammation and Renal Fibrosis

“…In healthy renal tissue, only a small number of lymphatic capillaries are distributed around the interlobular artery and interlobular vein, without distribution in the glomerulus and renal interstitium [45]. However, in chronic kidney diseases such as lupus nephritis, anti-neutrophil cytoplasmic antibody-related glomerulonephritis, tubulointerstitial nephritis, focal segmental glomerulosclerosis, crescentic glomerulonephritis, type II diabetic nephropathy, and IgA nephropathy, it shows markedly increased numbers of LVs compared to controls [8,46]. Numerous studies have shown that proteinuria induces the expression and release of chemokines and mediators in renal tubular epithelial cells, leading to inflammatory cell recruitment and kidney damage [46], which triggers intrarenal lymphangiogenesis before the onset of interstitial fibrosis.…”

“…However, in chronic kidney diseases such as lupus nephritis, anti-neutrophil cytoplasmic antibody-related glomerulonephritis, tubulointerstitial nephritis, focal segmental glomerulosclerosis, crescentic glomerulonephritis, type II diabetic nephropathy, and IgA nephropathy, it shows markedly increased numbers of LVs compared to controls [8,46]. Numerous studies have shown that proteinuria induces the expression and release of chemokines and mediators in renal tubular epithelial cells, leading to inflammatory cell recruitment and kidney damage [46], which triggers intrarenal lymphangiogenesis before the onset of interstitial fibrosis. In a rat proteinuric model, lymphangiogenesis occurred prior to macrophage influx, collagen deposition, and interstitial fibrosis, suggesting a possible pathogenetic role in fibrosis [45].…”

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

“…Multiple myeloma can be considered the best model to study plasma cells' role in lymphangiogenesis. Zimmer et al (2010) demonstrated that lymphangiogenesis is a prominent feature in multiple myeloma kidneys and that it is associated with a significant accumulation of macrophages, CD20 ? cells, and CD27 ?…”